胎儿室间隔缺损的产前遗传学检测策略:染色体核型分析、微阵列与外显子组测序的诊断效能比较

Prenatal genetic testing strategies for fetal ventricular septal defects:comparison of diagnostic efficacy among chromosome karyotyping,chromosomal microarray analysis and whole-exome sequencing

摘要

目的 探讨染色体核型分析、染色体微阵列分析(CMA)与全外显子组测序(WES)在产前诊断胎儿室间隔缺损(VSD)中的遗传学诊断价值。方法 选取2020年3月至2024年12月于安徽省妇女儿童医学中心行产前超声检查发现VSD的胎儿共204例,分为孤立性VSD组(Ⅰ组)69例;VSD合并其他心内畸形组(Ⅱ组)39例;VSD合并心外畸形组(Ⅲ组)29例;VSD合并软指标和/或高危因素组(Ⅳ组)67例。所有病例均行核型分析和CMA检测,经过充分的遗传咨询,最终14例核型及CMA检测结果阴性的胎儿及其父母选择进一步行WES检测。结果 204例产前超声发现室间隔缺损的胎儿样本中,核型分析共检出致病性遗传学异常13例,阳性检出率为6.37%(13/204),其中染色体非整倍体异常10例(76.92%)。亚组分析显示,VSD合并心外畸形组(Ⅲ组)核型分析阳性检出率为20.69%(6/29),高于孤立性VSD组(Ⅰ组)的1.45%(1/69),差异有统计学意义(Fisher确切概率法,P＜0.05);且Ⅲ组中非整倍体异常占17.24%(5/29),而Ⅰ组未检出非整倍体异常。在核型分析阴性的基础上CMA的额外检出率为3.14%(6/191),Ⅰ、Ⅱ、Ⅲ、Ⅳ组额外检出率分别为2.94%(2/68)、2.63%(1/38)、8.70%(2/23)、1.61%(1/62)。WES的额外检出率为21.43%(3/14)。结论 VSD合并心外畸形时,染色体异常风险显著增加,以染色体非整倍体异常最为常见。产前发现的所有VSD均建议进行以染色体核型分析联合CMA为基础的遗传学检测,必要时进一步行WES,若合并其他畸形推荐将CMA作为一线检测方法。

Abstract

Objective To evaluate genetic diagnostic value of chromosome karyotyping,chromosomal microarray analysis (CMA),and whole-exome sequencing (WES) for prenatally diagnosed fetal ventricular septal defects(VSD). Methods A total of 204 fetuses who were prenatally diagnosed as VSD by ultrasound at Anhui Women and Children's Medical Center from March 2020 to December 2024 were selected as study subjects and were categorized as follow four groups:isolated VSD group(Group Ⅰ,n=69),VSD accompanied with other intracardiac malformation group(Group Ⅱ,n=39),VSD accompanied with extracardiac malformation group(Group Ⅲ,n=29),and VSD accompanied with soft markers and/or high-risk factors group (Group Ⅳ,n=67).All fetuses were examined for karyotyping and CMA.After comprehensive genetic counseling,WES was performed on 14 fetuses with negative karyotyping and CMA results were screened,and they and their parents were examined for WES further. Results Karyotyping identified 13 cases of pathogenic genetic abnormalities,the positive detection rate was 6.37% (13/204),including 10 cases of aneuploidies (76.92%).Subgroup analysis revealed that the positive detection rate of pathogenic genetic abnormalities by karyotyping in the VSD accompanied with extracardiac malformations group (Group Ⅲ) was 20.69% (6/29),which was significantly higher than 1.45% (1/69) in the isolated VSD group (Group Ⅰ) and showed a significant difference between the two groups (Fisher's exact probability method,P＜0.05).And aneuploidy abnormalities accounted for 17.24% (5/29) of the cases in Group Ⅲ,whereas no aneuploidy abnormalities was detected in Group Ⅰ.CMA provided an incremental yield of 3.14% (6/191) of detection rate of pathogenic gefnetic abnormalities in those cases with negative karyotyping results,in detail,in groups Ⅰ,Ⅱ,Ⅲ and Ⅳ,the incremental detection rates were 2.94% (2/68),2.63% (1/38),8.70% (2/23) and 1.61%(1/62) respectively.WES demonstrated 21.43% (3/14) of incremental detection rate of pathogenic genetic chromosomal abnormalities. Conclusion Fetuses with VSD and extracardiac malformation exhibit a significantly increased risk of chromosomal abnormalities,predominantly aneuploidy.It is recommended that genetic testing based on chromosomal karyotyping combined with CMA should be done for all fetuses prenatally diagnosed as VSD,if necessary,WES should be conducted further.CMA should be prioritized as a first-tier test for VSD when other structural anomalies coexist.

关键词

胎儿 / 室间隔缺损 / 染色体微阵列分析 / 全外显子组测序 / 染色体核型分析 / 产前诊断

Key words

fetus / ventricular septal defect / chromosome microarray analysis / whole-exome sequencing / chromosomal karyotyping / prenatal diagnosis

参考文献

[1] Cruz-Lemini M, Nieto-Castro B, Luna-Garcia J, et al. Prenatal diagnosis of congenital heart defects:experience of the first Fetal Cardiology Unit in Mexico[J]. J Matern Fetal Neonatal Med, 2021, 34(10): 1529-1534.

[2] 赵华俊, 裴磊磊, 高显舜, 等. 安康市2017-2021年围产儿出生缺陷监测及先天性心脏病影响因素分析[J]. 中国妇幼健康研究, 2024, 35(5): 36-41.

[3] Liu Y, Chen S, Zühlke L, et al. Global birth prevalence of congenital heart defects 1970-2017:updated systematic review and meta-analysis of 260 studies[J]. Int J Epidemiol, 2019, 48(2): 455-463.

[4] Penny D J, Vick G W 3rd. Ventricular septal defect[J]. Lancet, 2011, 377(9771): 1103-1112.

[5] Adan A, Eleyan L, Zaidi M, et al. Ventricular septal defect:Diagnosis and treatments in the neonates:a systematic review[J]. Cardiol Young, 2021, 31(5): 756-761.

[6] Riggs E R, Andersen E F, Cherry A M, et al. Correction:Technical standards for the interpretation and reporting of constitutional copy-number variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2021, 23(11): 2230.

[7] Biesecker L G, Harrison S M. The ACMG/AMP reputable source criteria for the interpretation of sequence variants[J]. Genet Med, 2018, 20(12): 1687-1688.

[8] Zhang Y, Zhang W, Xu H, et al. Epidemiological Aspects,Prenatal Screening and Diagnosis of Congenital Heart Defects in Beijing [J]. Front Cardiovasc Med, 2021, 8: 777899.

[9] Zheng S Q, Chen H X, Liu X C, et al. Identification of variants of ISL1 gene promoter and cellular functions in isolated ventricular septal defects[J]. Am J Physiol Cell Physiol, 2021, 321(3): C443-C452.

[10] Mone F, Eberhardt R Y, Morris R K, et al. Congenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study:prospective cohort study and systematic review [J]. Ultrasound Obstet Gynecol, 2021, 57(1): 43-51.

[11] Shan W, Yuanqing X, Jing Z, et al. Risk factor analysis for adverse prognosis of the fetal ventricular septal defect (VSD)[J]. BMC Pregnancy Childbirth, 2023, 23(1): 683.

[12] Qiao F, Wang Y, Zhang C, et al. Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect[J]. Ultrasound Obstet Gynecol, 2021, 58(3): 377-387.

[13] Hailong H, Yan W, Min Z, et al. Diagnostic accuracy and value of chromosomal microarray analysis for chromosomal abnormalities in prenatal detection:A prospective clinical study[J]. Medicine (Baltimore), 2021, 100(20): e25999.

[14] Cheng K, Zhou H, Fu F, et al. Should prenatal chromosomal microarray analysis be offered for isolated ventricular septal defect? A single-center retrospective study from China[J]. Front Cardiovasc Med, 2022, 9: 988438.

[15] Zhao X, Shen Y, Kong D, et al. Correlation between types of ventricular septal defect and chromosomal abnormalities in low-risk non-invasive prenatal testing [J]. Arch Gynecol Obstet, 2024, 310(3): 1517-1523.

[16] Lu Q, Luo L, Zeng B, et al. Prenatal chromosomal microarray analysis in a large Chinese cohort of fetuses with congenital heart defects:a single center study[J]. Orphanet J Rare Dis, 2024, 19(1): 307.

[17] Hu H, Zhou B, Shan Q, et al. Genetic test results and one-year developmental outcomes of fetuses with congenital heart disease [J]. Front Pediatr, 2025, 13: 1518784.

[18] Zhang S, Wang J, Pei Y, et al. Diagnostic value of chromosomal microarray analysis for fetal congenital heart defects with different cardiac phenotypes and extracardiac abnormalities[J]. Diagnostics (Basel), 2023, 13(8): 1493.

[19] 曾丹, 范舒舒, 徐静, 等. 核型正常产前诊断中染色体微阵列的应用分析[J]. 中国妇幼健康研究, 2024, 35(11): 85-91.

[20] Van den Veyver I B, Chandler N, Wilkins-Haug L E, et al. International Society for Prenatal Diagnosis Updated Position Statement on the use of genome-wide sequencing for prenatal diagnosis[J]. Prenat Diagn, 2022, 42(6): 796-803.

[21] Li R, Fu F, Yu Q, et al. Prenatal exome sequencing in fetuses with congenital heart defects[J]. Clinical genetics, 2020, 98(3): 215-230.

[22] Wang Y, Li R, Fu F, et al. Prenatal genetic diagnosis associated with fetal ventricular septal defect:an assessment based on chromosomal microarray analysis and exome sequencing[J]. Front Genet, 2023, 14: 1260995.

[23] Jin S C, Homsy J, Zaidi S, et al. Contribution of rare inherited and de novo variants in 2 871 congenital heart disease probands[J]. Nat Genet, 2017, 49(11): 1593-1601.

[24] Yi K, He S E, Guo T, et al. Association of MTHFD1 G1958A (rs2236225) gene polymorphism with the risk of congenital heart disease:a systematic review and meta-analysis[J]. BMC Med Genomics, 2025, 18(1): 20.

[25] El-Dessouky S H, Issa M Y, Aboulghar M M, et al. Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant[J]. Am J Med Genet A, 2020, 182(12): 2867-2876.

[26] Josifova D J, Monroe G R, Tessadori F, et al. Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia,intellectual disability,nystagmus,and obesity [J]. Hum Mol Genet, 2016, 25(11): 2158-2167.

[27] Sierant M C, Jin S C, Bilguvar K, et al. Genomic analysis of 11 555 probands identifies 60 dominant congenital heart disease genes[J]. Proc Natl Acad Sci U S A, 2025, 122(13): e2420343122.

基金资助

安徽省高校自然科学基金重点项目(2023AH050575)